Design,Synthesis,and Biological Activity Studies Of Novel,Urea PTP1B Inhibitors

The incidence of diabetes is the most extensive disease in the world.Diabetes is due to lack of insulin or the body cannot effectively use the insulin(ie insulin resistance(Insulin Resistance,IR))caused by a disease of glucose metabolism disorders.The diabetic patients were divided into two categories,that type I diabetes(insulin-dependent diabetes mellitus(IDDM))and type II diabetes(non-insulin-dependent diabetes mellitus(N1DDM)).Because the causes of type II diabetes is very complex,making treatment very difficult,there is no cure drug,and therefore to carry out anti-diabetic drug discovery has very important significance.This paper mainly for type ? diabetes is an important target for PTP1B,using computer-aided molecular modeling and virtual screening techniques were designed to study the anti-diabetic drugs.Protein tyrosine phosphatase 1B(PTP1B)is a negative regulator of the insulin and leptin receptor pathways.PTP1B deficient mice were viable,healthy,and lean and they displayed enhanced insulin sensitivity and resistance todiet-induced obesity.This provides important evidence thatPTP1B inhibition would be an effective diabetes therapy.It has been extensively studied within academia and thepharmaceutical industry and is regarded by many as one of the best validated drug targets for intervention in type ? diabetes and obesity.The main work of this paper is to study:the computer-aided molecular modeling and virtual screening techniques for PTP1B inhibitors were used to designed and synthesized for a total of 33 compounds.This compound is the first time that sulfonamido and ureido groups were together used in the PTP1B inhibitors.The 33 synthesized compounds exhibited varying degrees of PTP1B inhibitory activity in vitro activity screening,and the IC50 of the target product 10a?19a is 19.8 nM and 18.6 nM.We selected 11 pairs of strong activity compounds which have strong PTP1B Inhibitory activity using to do binding activity test.The results prove that 11 compounds are reflected on the selective inhibition of PTP1B better relative to TCPTP,SHP1,SHP2,LAR,and study onStructure-activity relationship.